Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

FEV1 Predicts Cardiac Status and Outcome in Chronic Heart Failure.

BACKGROUND: COPD is an established predictor of clinical outcome in patients with chronic heart failure (HF). However, little evidence is available about the predictive value of FEV1 in chronic HF. RESEARCH QUESTION: Is pulmonary function related to the progression of chronic HF? STUDY DESIGN AND METHODS: The MyoVasc study (ClinicalTrials.gov Identifier: NCT04064450) is a prospective cohort study of HF. Information on pulmonary and cardiac functional and structural status was obtained by body plethysmography and echocardiography. The primary study end point was worsening of HF. RESULTS: Overall 2,998 participants (age range, 35-84 years) with available FEV1 data were eligible for analysis. Linear multivariate regression analysis revealed an independent relationship of FEV1 (per -1 SD) with deteriorated systolic and diastolic left ventricle (LV) function as well as LV hypertrophy under adjustment of age, sex, height, cardiovascular risk factors (CVRFs), and clinical profile (LV ejection fraction: ß-estimate, -1.63% [95% CI, -2.00% to -1.26%]; E/E' ratio: ß-estimate, 0.82 [95% CI, 0.64-0.99]; and LV mass/height2.7: ß-estimate, 1.58 [95% CI, 1.07-2.10]; P < .001 for all). During a median time to follow-up of 2.6 years (interquartile range, 1.1-4.1 years), worsening of HF occurred in 235 individuals. In Cox regression model adjusted for age, sex, height, CVRF, and clinical profile, pulmonary function (FEV1 per -1 SD) was an independent predictor of worsening of HF (hazard ratio [HR], 1.44 [95% CI, 1.27-1.63]; P < .001). Additional adjustment for obstructive airway pattern and C-reactive protein mitigated, but did not substantially alter, the results underlining the robustness of the observed effect (HRFEV1, 1.39 [95% CI, 1.20-1.61]; P < .001). The predictive value of FEV1 was consistent across subgroups, including individuals without obstruction (HR, 1.55 [95% CI, 1.34-1.77]; P < .001) and nonsmokers (HR, 1.72 [95% CI, 1.39-1.96]; P < .001). INTERPRETATION: FEV1 represents a strong candidate to improve future risk stratification and prevention strategies in individuals with chronic, stable HF. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04064450; URL: www.clinicaltrials.gov.